Genetic and pharmacological inhibition of TTK impairs pancreatic cancer cell line growth by inducing lethal chromosomal instability

Public Deposited
Analytics

Downloadable Content

Download PDF
Request Version for Screen Reader
Creator
  • Stratford, Jeran K.
    • Affiliation: School of Medicine, Department of Pharmacology
    • Other Affiliation: University of North Carolina at Chapel Hill
  • Yan, Feng
    • Affiliation: University of North Carolina at Chapel Hill
  • Hill, Rebecca A.
    • Affiliation: University of North Carolina at Chapel Hill
  • Major, Michael B.
    • Affiliation: University of North Carolina at Chapel Hill
    • Other Affiliation: Department of Computer Science
  • Graves, Lee M.
    • Affiliation: School of Medicine, Department of Pharmacology
    • Other Affiliation: University of North Carolina at Chapel Hill
  • Der, Channing J.
    • Affiliation: School of Medicine, Department of Pharmacology
    • Other Affiliation: University of North Carolina at Chapel Hill
  • Yeh, Jen Jen
    • Affiliation: School of Medicine, Department of Pharmacology
    • Other Affiliation: University of North Carolina at Chapel Hill
Abstract
  • Pancreatic ductal adenocarcinoma, which accounts for the majority of pancreatic cancers, is a lethal disease with few therapeutic options. Genomic profiling of pancreatic ductal adenocarcinoma has identified a complex and heterogeneous landscape. Understanding the molecular characteristics of pancreatic ductal adenocarcinoma will facilitate the identification of potential therapeutic strategies. We analyzed the gene expression profiles of primary tumors from patients compared to normal pancreas and identified high co-overexpression of core components of the spindle assembly checkpoint, including the protein kinase TTK (also known as MPS-1). We found overexpression of TTK protein in a subset of pancreatic ductal adenocarcinoma primary tumors and cell lines. siRNA-mediated depletion or catalytic inhibition of TTK resulted in an aberrant cell cycle profile, multi- and micro-nucleation, induction of apoptosis, and decreased cell proliferation and transformed growth. Selective catalytic inhibition of TTK caused override of the spindle assembly checkpoint-induced cell cycle arrest. Interestingly, we identified ubiquitin specific peptidase 16 (Usp16), an ubiquitin hydrolase, as a phosphorylation substrate of TTK. Usp16 regulates chromosomal condensation and G2/M progression by deubiquitinating histone H2A and polo-like kinase 1. Phosphomimetic mutants of Usp16 show enhanced proteosomal degradation and may prolong the G2/M transition allowing for correction of replication errors. Taken together, our results suggest a critical role for TTK in preventing aneuploidy-induced cell death in pancreatic cancer.
Date of publication
Keyword
DOI
Identifier
Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • PloS One
Journal volume
  • 12
Journal issue
  • 4
Page start
  • e0174863
Language
  • English
ISSN
  • 1932-6203

Relations

Parents:

This work has no parents.

In Collection:

Items

Thumbnail Title Date Uploaded Visibility Actions
file details PubMedCentral-PMC5381904.pdf 2017 Public Download